Inhibitors of farnesyl protein transferase

ABSTRACT

This invention relates to compounds of formula (I) that inhibit farnesylation of gene products through inhibition of the enzyme farnesyl-protein transferase (FPTase). The invention also relates to methods of manufacturing the compounds, pharmaceutical compositions and methods of treating diseases, especially cancer, which are mediated through farnesylation.

[0001] This invention relates to compounds that inhibit farnesylation ofmutant ras gene products through inhibition of the enzymefarnesyl-protein transferase (FPTase). The invention also relates tomethods of manufacturing the compounds, pharmaceutical compositions andmethods of treating diseases, especially cancer, which are mediatedthrough farnesylation.

[0002] Cancer is believed to involve alteration in expression orfunction of genes controlling cell growth and differentiation. Whilstnot wishing to be bound by theoretical considerations the following textsets out the scientific background to ras in cancer. Ras genes arefrequently mutated in tumours. Ras genes encode guanosine triphosphate(GTP) binding proteins which are believed to be involved in signaltransduction, proliferation and malignant transformation. H-, K- andN-ras genes have been identified as mutant forms of ras (Barbacid M,Ann. Rev. Biochem. 1987, 56: 779-827). Post translational modificationof ras protein is required for biological activity. Farnesylation of rascatalysed by FPTase is believed to be an essential step in rasprocessing. It occurs by transfer of the farnesyl group of farnesylpyrophosphate (FPP) to a cysteine at the C-terminal tetrapeptide of rasin a structural motif called the CAAX box. After furtherpost-translational modifications, including proteolytic cleavage at thecysteine residue of the CAAX box and methylation of the cysteinecarboxyl, ras is able to attach to the cell membrane for relay of growthsignals to the cell interior. In normal cells activated ras is believedto act in conjunction with growth factors to stimulate cell growth. Intumour cells it is believed that mutations in ras cause it to stimulatedivision even in the absence of growth factors (Travis J, Science 1993,260: 1877-1878), possibly through being permanently in GTP activatedform rather than cycled back to GDP inactivated form. Inhibition offarnesylation of mutant ras gene products will stop or reduceactivation.

[0003] One class of known inhibitors of farnesyl transferase is based onfarnesyl pyrophosphate analogues; see for example European patentapplication EP 534546 from Merck. Inhibitors of farnesyl transferasebased on mimicry of the CAAX box have been reported. Reiss (1990) inCell 62, 81-8 disclosed tetrapeptides such as CVIM (Cys-Val-Ile-Met).James (1993) in Science 260, 1937-1942 disclosed benzodiazepine basedpeptidomimetic compounds. Lerner (1995) in J. Biol. Chem. 270, 26802 andEisai in International Patent Application WO 95/25086 disclosed furtherpeptidomimetic compounds based on Cys as the first residue. EP 696593and PCT/GB96/01810 disclose further farnesyl transferase inhibitors,including pyrrolidine derivatives.

[0004] The applicants have found that a particular substitution of thepyrrolidine provides particular advantages in terms of inhibition offarnesyl transferase.

[0005] According to one aspect of the present invention there isprovided a compound of formula (I)

[0006] wherein:

[0007] R¹ and R² are independently selected from H or a prodrug moiety;

[0008] R³ is hydrogen or halogen;

[0009] R⁴ is hydrogen or halogen;

[0010] L is —CH═CH— or —CH₂—Z— where Z is NH or O;

[0011] Y is S, S(O) or S(O)₂;

[0012] or a salt thereof, provided that at least one of R³ or R⁴ isother than hydrogen.

[0013] As used herein, the term “alkyl” refers to straight-or branchedchain groups, which may, unless otherwise stated have from 1 to 20 andpreferably from 1 to 6 carbon atoms. The term “aryl” includes phenyl.The term “halo” includes fluoro, chloro, bromo and iodo.

[0014] The term “heterocyclyl” or “heterocyclic” include groups havingfrom 4 to 10 ring atoms, up to 5 of which are selected from oxygen,sulphur and nitrogen. The rings may be mono-, or bicyclic and each ringmay be aromatic or non-aromatic in character. Nitrogen atoms may besubstituted if the valency of the ring allows it, with either a hydrogenor substituent group, such as a alkyl substituent. Sulphur atoms in aheterocyclic ring may be oxidised to S(O) or S(O)₂ groups.

[0015] Examples of aromatic 5- or 6-membered heterocyclic ring systemsinclude imidazole, triazole, pyrazine, pyrimidine, pyridazine, pyridine,isoxazole, oxazole, isothiazole, thiazole and thiophene. A 9- or10-membered bicyclic heteroaryl ring system is an aromatic bicyclic ringsystem comprising a 6-membered ring fused to either a 5 membered ring oranother 6 membered ring. Examples of 5/6 and 6/6 bicyclic ring systemsinclude benzofuran, benzimidazole, benzthiophene, benzthiazole,benzisothiazole, benzoxazole, benzisoxazole, pyridoimidazole,pyrimidoimidazole, quinoline, isoquinoline, quinoxaline, quinazoline,phthalazine, cinnoline and naphthyridine.

[0016] Preferably monocyclic heteroaryl rings contain up to 3heteroatoms and bicyclic heteroaryl rings contain up to 5 heteroatoms.Preferred heteroatoms are N and S, especially N. In general, attachmentof heterocyclic rings to other groups is via carbon atoms. Suitableheterocyclic groups containing only N as the heteroatom are pyrrole,pyridine, indole, quinoline, isoquinoline, imidazole, pyrazine,pyrimidine, purine and pteridine.

[0017] Hydrogenated or other substituted forms of the above aromaticrings, (which are not aromatic), such as tetrahydropyridyl rings areexamples of non-aromatic heterocyclic groups.

[0018] Various forms of prodrugs are known in the art. For examples ofsuch prodrug derivatives, see:

[0019] a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985)and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, etal. (Academic Press, 1985);

[0020] b) A Textbook of Drug Design and Development, edited byKrogsgaard-Larsen;

[0021] c) H. Bundgaard, Chapter 5 “Design and Application of Prodrugs”,by H. Bundgaard p. 113-191 (1991);

[0022] d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);

[0023] e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77,285 (1988); and

[0024] f) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).

[0025] Suitable examples of groups R¹ are hydrogen or prodrug groups offormula R⁵C(O)— where R⁵ is an optionally substituted aryl orheterocyclyl group. In particular R⁵ is optionally substituted phenyl,optionally substituted pyridyl optionally substituted furyl, optionallysubstituted isoxazole, optionally substituted tetrahydropyridyl oroptionally substituted tetrahydrofuryl.

[0026] Suitable substituents for R⁵ include alkyl groups such as methyl,haloalkyl groups such as trifluoromethyl, hydroxy, alkoxy such asmethoxy or cyano.

[0027] Preferably R⁵ is phenyl, pyridyl or N-methyl-tetrahydropyridyl.

[0028] Examples of prodrugs groups for R² are in vivo cleavable estergroups of a pharmaceutically-acceptable ester which is cleaved in thehuman or animal body to produce the parent acid. Suitably R² togetherwith the carboxy group to which it is attached forms apharmaceutically-acceptable esters such as C₁₋₆alkyl esters orC₁₋₆cycloalkyl esters, for example methyl, ethyl, propyl, iso-propyl,n-butyl or cyclopentyl; C₁₋₆alkoxymethyl esters, for examplemethoxymethyl; C₁₋₆alkanoyloxymethyl esters, for examplepivaloyloxymethyl; phthalidyl esters;C₃₋₈cycloalkoxycarbonyloxyC₁₋₆alkyl esters, for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolan-2-ylmethyl esters, forexample 5-methyl-1,3-dioxolan-2-ylmethyl; C₁₋₆alkoxycarbonyloxyethylesters, for example 1-methoxycarbonyloxyethyl; aminocarbonylmethylesters and mono- or di-N—(C₁₋₆alkyl) versions thereof, for exampleN,N-dimethylaminocarbonylmethyl esters and N-ethylaminocarbonylmethylesters, and pharmaceutically acceptable esters of optionally substitutedheterocyclic groups.

[0029] Further examples of such prodrugs for R² are in vivo cleavableamides of a compound of the invention. Suitably R² together with thecarboxy group to which it is attached forms apharmaceutically-acceptable amide, preferably an N—C₁₋₆alkylamide and anN,N-di-(C₁₋₆alkyl)amide, such as N-methyl, N-ethyl, N-propyl,N,N-dimethyl, N-ethyl-N-methyl or N,N-diethylamide.

[0030] Thus in particular, R² is selected from hydrogen, a C₁₋₄alkylgroup such as isopropyl or cyclopentyl, or an optionally substitutedheterocyclic group such as N-methyl-tetrahydropyridyl.

[0031] R³ is suitably a halo atom such as fluoro or chloro group, inparticular fluorine.

[0032] R⁴ is preferably a hydrogen or fluorine, and in particular ishydrogen.

[0033] The linking group L is suitably a group of formula CH₂—Z— where Zis NH or O.

[0034] Preferably the linking group L is —CH═CH—. Both E and Z isomericforms of such compounds form part of the invention together withmixtures thereof. In particular, compounds were geometrical isomerism ispossible are preferably in E form.

[0035] Group Y is preferably a group S or S(O)₂. It is to be understoodthat, insofar as certain of the compounds of Formula I defined above mayexist in optically active or racemic forms by virtue of one or moreasymmetric carbon atoms, the invention includes in its definition anysuch optically active or racemic form which possesses the property ofinhibiting FTPase. The synthesis of optically active forms may becarried out by standard techniques of organic chemistry well known inthe art, for example by synthesis from optically active startingmaterials or by resolution of a racemic form. Similarly, inhibitoryproperties against FTPase may be evaluated using the standard laboratorytechniques referred to hereinafter.

[0036] Chiral carbon atoms at the 2 and 4 positions of the pyrrolidinering in Formula I are preferred in the (S) configuration.

[0037] The chiral carbon atom at the 2 position between the carbonyl andamine in Formula I is preferred in the (S) configuration.

[0038] Compounds of Formula I may form salts which are within the ambitof the invention. Pharmaceutically acceptable salts are preferredalthough other salts may be useful in, for example, isolating orpurifying compounds.

[0039] When the compound contains a basic moiety it may formpharmaceutically acceptable salts with a variety of inorganic or organicacids, for example hydrochloric, hydrobromic, sulphuric, phosphoric,trifluoroacetic, citric or maleic acid. A suitablepharmaceutically-acceptable salt of the invention when the compoundcontains an acidic moiety is an alkali metal salt, for example a sodiumor potassium salt, an alkaline earth metal salt, for example a calciumor magnesium salt, an ammonium salt or a salt with an organic base whichaffords a pharmaceutically-acceptable cation, for example a salt withmethylamine, dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine. Particular salts of compounds of theinvention are acetates, alkyl sulphonates such as methyl or ethylsulphonate, fumarates, formates, succinates and gluconates.

[0040] Solvates, for example hydrates, are also within the ambit of theinvention and may be prepared by generally known methods.

[0041] Particular examples of compounds of formula (I) are shown inTable 1 TABLE 1

Compd. No R¹ R² R³ L Y 1 H H F —CH═CH— S (E form) 2 H

F —CH═CH—(E form) S 3 H —CH(CH₃)₂ F —CH═CH— S (E form) 4

F —CH₂O— S 5

—CH(CH₃)₂ F —CH═CH—(E form) S 6 H H F —CH₂NH— S 7 H —CH(CH₃)₂ F —CH₂NH—S 8

—CH(CH₃)₂ F —CH₂NH— S 9

F —CH═CH— S

[0042] According to another aspect of the invention there is provided acompound of Formula I for use as a medicament.

[0043] Further according to the invention there is provided a compoundof Formula I for use in preparation of a medicament for treatment of adisease mediated through farnesylation of ras, in particular cancer.

[0044] The compound is suitably formulated as a pharmaceuticalcomposition for use in this way.

[0045] Thus, according to yet another aspect of the invention there isprovided a pharmaceutical composition comprising a compound of formula Ilisted above together with a pharmaceutically acceptable diluent orcarrier.

[0046] According to another aspect of the present invention there isprovided a method of treating ras mediated diseases, especially cancer,by administering an effective amount of a compound of Formula I to amammal in need of such treatment.

[0047] According to a further feature of the invention there is provideda compound of Formula I, or a pharmaceutically-acceptable salt thereof,for use in a method of treatment of the human or animal body by therapy.

[0048] The invention also provides the use of a compound of formula (I)in the preparation of a medicament for use in treating farnesylated rasmediated disease or medical condition such as cancers.

[0049] Specific cancers which may be treated by the compound orcomposition of the invention include:

[0050] carcinoma, including that of the bladder, breast, colon, kidney,liver, lung, ovary, pancreas, stomach, cervix, thyroid and skin;

[0051] hematopoietic tumors of lymphoid lineage, including acutelymphocytic leukemia, B-cell lymphoma and Burketts lymphoma;

[0052] hematopoietic tumors of myeloid lineage, including acute andchronic myelogenous leukemias and promyelocytic leukemia;

[0053] tumors of mesenchymal origin, including fibrosarcoma andrhabdomyosarcoma; and

[0054] other tumors, including melanoma, seminoma, tetratocarcinoma,neuroblastoma and glioma. The compounds of Formula I are especiallyuseful in treatment of tumors having a high incidence of ras mutation,such as colon, lung, and pancreatic tumors. By the administration of acomposition having one (or a combination) of the compounds of thisinvention, development of tumors in a mammalian host is reduced.

[0055] Compounds of Formula I may also be useful in the treatment ofdiseases other than cancer that may be associated with signaltransduction pathways operating through Ras, e.g., neuro-fibromatosis.

[0056] Compounds of Formula I may also be useful in the treatment ofdiseases associated with CAAX-containing proteins other than Ras (e.g.,nuclear lamins and transducin) that are also post-translationallymodified by the enzyme farnesyl protein transferase.

[0057] The compositions of the invention may be in a form suitable fororal use (for example as tablets, lozenges, hard or soft capsules,aqueous or oily suspensions, emulsions, dispersible powders or granules,syrups or elixirs), for topical use (for example as creams, ointments,gels, or aqueous or oily solutions or suspensions), for administrationby inhalation (for example as a finely divided powder or a liquidaerosol), for administration by insufflation (for example as a finelydivided powder) or for parenteral administration (for example as asterile aqueous or oily solution for intravenous, subcutaneous,intramuscular or intramuscular dosing or as a suppository for rectaldosing).

[0058] The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

[0059] Suitable pharmaceutically acceptable excipients for a tabletformulation include, for example, inert diluents such as lactose, sodiumcarbonate, calcium phosphate or calcium carbonate, granulating anddisintegrating agents such as corn starch or algenic acid; bindingagents such as starch; lubricating agents such as magnesium stearate,stearic acid or talc; preservative agents such as ethyl or propylp-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tabletformulations may be uncoated or coated either to modify theirdisintegration and the subsequent absorption of the active ingredientwithin the gastrointestinal tract, or to improve their stability and/orappearance, in either case, using conventional coating agents andprocedures well known in the art.

[0060] Compositions for oral use may be in the form of hard gelatincapsules in which the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules in which the active ingredient is mixed withwater or an oil such as peanut oil, liquid paraffin, or olive oil.

[0061] Aqueous suspensions generally contain the active ingredient infinely powdered form together with one or more suspending agents, suchas sodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone,gum tragacanth and gum acacia; dispersing or wetting agents such aslecithin or condensation products of an alkylene oxide with fatty acids(for example polyoxethylene stearate), or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives (such as ethyl orpropyl p-hydroxybenzoate; anti-oxidants (such as ascorbic acid),colouring agents, flavouring agents, and/or sweetening agents (such assucrose, saccharine or aspartame).

[0062] Oily suspensions may be formulated by suspending the activeingredient in a vegetable oil (such as arachis oil, olive oil, sesameoil or coconut oil) or in a mineral oil (such as liquid paraffin). Theoily suspensions may also contain a thickening agent such as beeswax,hard paraffin or cetyl alcohol. Sweetening agents such as those set outabove, and flavouring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

[0063] Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water generally contain the activeingredient together with a dispersing or wetting agent, suspending agentand one or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients such as sweetening, flavouring and colouringagents, may also be present.

[0064] The pharmaceutical compositions of the invention may also be inthe form of oil-in-water emulsions. The oily phase may be a vegetableoil, such as olive oil or arachis oil, or a mineral oil, such as forexample liquid paraffin or a mixture of any of these. Suitableemulsifying agents may be, for example, naturally-occurring gums such asgum acacia or gum tragacanth, naturally-occurring phosphatides such assoya bean, lecithin, an esters or partial esters derived from fattyacids and hexitol anhydrides (for example sorbitan monooleate) andcondensation products of the said partial esters with ethylene oxidesuch as polyoxyethylene sorbitan monooleate. The emulsions may alsocontain sweetening, flavouring and preservative agents.

[0065] Syrups and elixirs may be formulated with sweetening agents suchas glycerol, propylene glycol, sorbitol, aspartame or sucrose, and mayalso contain a demulcent, preservative, flavouring and/or colouringagent.

[0066] The pharmaceutical compositions may also be in the form of asterile injectable aqueous or oily suspension, which may be formulatedaccording to known procedures using one or more of the appropriatedispersing or wetting agents and suspending agents, which have beenmentioned above. A sterile injectable preparation may also be a sterileinjectable solution or suspension in a non-toxic parenterally-acceptablediluent or solvent, for example a solution in 1,3-butanediol.

[0067] Suppository formulations may be prepared by mixing the activeingredient with a suitable non-irritating excipient which is solid atordinary temperatures but liquid at the rectal temperature and willtherefore melt in the rectum to release the drug. Suitable excipientsinclude, for example, cocoa butter and polyethylene glycols.

[0068] Topical formulations, such as creams, ointments, gels and aqueousor oily solutions or suspensions, may generally be obtained byformulating an active ingredient with a conventional, topicallyacceptable, vehicle or diluent using conventional procedure well knownin the art.

[0069] Compositions for administration by insufflation may be in theform of a finely divided powder containing particles of average diameterof, for example, 30μ or much less, the powder itself comprising eitheractive ingredient alone or diluted with one or more physiologicallyacceptable carriers such as lactose. The powder for insufflation is thenconveniently retained in a capsule containing, for example, 1 to 50 mgof active ingredient for use with a turbo-inhaler device, such as isused for insufflation of the known agent sodium cromoglycate.

[0070] Compositions for administration by inhalation may be in the formof a conventional pressurised aerosol arranged to dispense the activeingredient either as an aerosol containing finely divided solid orliquid droplets. Conventional aerosol propellants such as volatilefluorinated hydrocarbons or hydrocarbons may be used and the aerosoldevice is conveniently arranged to dispense a metered quantity of activeingredient.

[0071] For further information on Formulation the reader is referred toChapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (CorwinHansch; Chairman of Editorial Board), Pergamon Press 1990.

[0072] The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 2 g of active agent compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition. Dosage unit forms will generallycontain about 1 mg to about 500 mg of an active ingredient. For furtherinformation on Routes of Administration and Dosage Regimes the reader isreferred to Chapter 25.3 in Volume 5 of Comprehensive MedicinalChemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press1990.

[0073] The size of the dose for therapeutic or prophylactic purposes ofa compound of the Formula I will naturally vary according to the natureand severity of the conditions, the age and sex of the animal or patientand the route of administration, according to well known principles ofmedicine. As mentioned above, compounds of the Formula I are useful intreating diseases or medical conditions which are due alone or in partto the effects of farnesylation of ras.

[0074] In using a compound of the Formula I for therapeutic orprophylactic purposes it will generally be administered so that a dailydose in the range, for example, 0.5 mg to 75 mg per kg body weight isreceived, given if required in divided doses. In general lower doseswill be administered when a parenteral route is employed. Thus, forexample, for intravenous administration, a dose in the range, forexample, 0.5 mg to 30 mg per kg body weight will generally be used.Similarly, for administration by inhalation, a dose in the range, forexample, 0.5 mg to 25 mg per kg body weight will be used. Oraladministration is however preferred.

[0075] Compounds of this invention may be useful in combination withknown anti-cancer and cytotoxic agents. If formulated as a fixed dosesuch combination products employ the compounds of this invention withinthe dosage range described herein and the other pharmaceutically activeagent within its approved dosage range. Sequential use is contemplatedwhen a combination formulation is inappropriate.

[0076] Although the compounds of the Formula I are primarily of value astherapeutic agents for use in warm-blooded animals (including man), theyare also useful whenever it is required to inhibit the effects ofactivation of ras by farnesylation. Thus, they are useful aspharmacological standards for use in the development of new biologicaltests and in the search for new pharmacological agents.

[0077] According to another aspect of the present invention there isprovided individual compounds produced as end products in the Examplesset out below and salts thereof.

[0078] A compound of the invention, or a salt thereof, may be preparedby any process known to be applicable to the preparation ofsuch-compounds or structurally related compounds. Such processes areillustrated by the following representative schemes in which variablegroups have any of the meanings defined for Formula I unless statedotherwise. Functional groups may be protected and deprotected usingconventional methods. For examples of protecting groups such as aminoand carboxylic acid protecting groups (as well as means of formation andeventual deprotection), see T. W. Greene and P. G. M. Wuts, “ProtectiveGroups in Organic Synthesis”, Second Edition, John Wiley & Sons, NewYork, 1991. Note abbreviations used have been listed immediately beforethe Examples below.

[0079] Protecting groups may be removed by any convenient method asdescribed in the literature or known to the skilled chemist asappropriate for the removal of the protecting group in question, suchmethods being chosen so as to effect removal of the protecting groupwith minimum disturbance of groups elsewhere in the molecule.

[0080] Specific examples of protecting groups are given below for thesake of convenience, in which “lower” signifies that the group to whichit is applied preferably has 1-4 carbon atoms. It will be understoodthat these examples are not exhaustive. Where specific examples ofmethods for the removal of protecting groups are given below these aresimilarly not exhaustive. The use of protecting groups and methods ofdeprotection not specifically mentioned is of course within the scope ofthe invention.

[0081] A carboxy protecting group may be the residue of an ester-formingaliphatic or araliphatic alcohol or of an ester-forming silanol (thesaid alcohol or silanol preferably containing 1-20 carbon atoms).

[0082] Examples of carboxy protecting groups include straight orbranched chain (1-12C)alkyl groups (e.g. isopropyl, t-butyl); loweralkoxy lower alkyl groups (e.g. methoxymethyl, ethoxymethyl,isobutoxymethyl; lower aliphatic acyloxy lower alkyl groups, (e.g.acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl);lower alkoxycarbonyloxy lower alkyl groups (e.g.1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl); aryl lower alkylgroups (e.g. p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryland phthalidyl); tri(lower alkyl)silyl groups (e.g. trimethylsilyl andt-butyldimethylsilyl); tri(lower alkyl)silyl lower alkyl groups (e.g.trimethylsilylethyl); and (2-6C)alkenyl groups (e.g. allyl andvinylethyl).

[0083] Methods particularly appropriate for the removal of carboxylprotecting groups include for example acid-, metal- orenzymically-catalysed hydrolysis.

[0084] Examples of hydroxy protecting groups include lower alkenylgroups (e.g. allyl); lower alkanoyl groups (e.g. acetyl); loweralkoxycarbonyl groups (e.g. t-butoxycarbonyl); lower alkenyloxycarbonylgroups (e.g. allyloxycarbonyl); aryl lower alkoxycarbonyl groups (e.g.benzoyloxycarbonyl, p-methoxybenzyloxycarbonyl,o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl); tri loweralkyl/arylsilyl groups (e.g. trimethylsilyl, t-butyldimethylsilyl,t-butyldiphenylsilyl); aryl lower alkyl groups (e.g. benzyl) groups; andtriaryl lower alkyl groups (e.g. triphenylmethyl).

[0085] Examples of amino protecting groups include formyl, aralkylgroups (e.g. benzyl and substituted benzyl, e.g. p-methoxybenzyl,nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl);di-p-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (e.g.t-butoxycarbonyl); lower alkenyloxycarbonyl (e.g. allyloxycarbonyl);aryl lower alkoxycarbonyl groups (e.g. benzyloxycarbonyl,p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl,p-nitrobenzyloxycarbonyl; trialkylsilyl (e.g. trimethylsilyl andt-butyldimethylsilyl); alkylidene (e.g. methylidene); benzylidene andsubstituted benzylidene groups.

[0086] Methods appropriate for removal of hydroxy and amino protectinggroups include, for example, acid-, base, metal- orenzymically-catalysed hydrolysis, or photolytically for groups such aso-nitrobenzyloxycarbonyl, or with fluoride ions for silyl groups.

[0087] Examples of protecting groups for amide groups includearalkoxymethyl (e.g. benzyloxymethyl and substituted benzyloxymethyl);alkoxymethyl (e.g. methoxymethyl and trimethylsilylethoxymethyl); trialkyl/arylsilyl (e.g. trimethylsilyl, t-butyldimethylsily,t-butyldiphenylsilyl); tri alkyl/arylsilyloxymethyl (e.g.t-butyldimethylsilyloxymethyl, t-butyldiphenylsilyloxymethyl);4-alkoxyphenyl (e.g. 4-methoxyphenyl); 2,4-di(alkoxy)phenyl (e.g.2,4-dimethoxyphenyl); 4-alkoxybenzyl (e.g. 4-methoxybenzyl);2,4-di(alkoxy)benzyl (e.g. 2,4-di(methoxy)benzyl); and alk-1-enyl (e.g.allyl, but-1-enyl and substituted vinyl e.g. 2-phenylvinyl).

[0088] Aralkoxymethyl, groups may be introduced onto the amide group byreacting the latter group with the appropriate aralkoxymethyl chloride,and removed by catalytic hydrogenation. Alkoxymethyl, trialkyl/arylsilyl and tri alkyl/silyloxymethyl groups may be introduced byreacting the amide with the appropriate chloride and removing with acid;or in the case of the silyl containing groups, fluoride ions. Thealkoxyphenyl and alkoxybenzyl groups are conveniently introduced byarylation or alkylation with an appropriate halide and removed byoxidation with ceric ammonium nitrate. Finally alk-1-enyl groups may beintroduced by reacting the amide with the appropriate aldehyde andremoved with acid.

[0089] The invention also provides a process for preparing a compound offormula (I) as defined above which process The invention also provides aprocess for preparing a compound of formula (I) as defined above whichprocess comprises reacting a compound of formula (II)

[0090] where L, R³ and R⁴ are as defined in relation to formula (I),R^(1′) is a group R¹ as defined in relation to formula (I) or aprecursor thereof, and R⁵ is a protecting group such as BOC or ALLOCwith a compound of formula (III)

[0091] where Y is as defined in relation to formula (I) and R^(2′) is agroup R² as defined in relation to formula (I) or a precursor thereof;

[0092] and thereafter if desired or necessary, carrying out one or moreof the following steps:

[0093] a) removing protecting groups R⁵;

[0094] a) converting any precursor groups R^(1′) and R^(2′) to groups R¹and R²; and

[0095] b) changing said groups to different R¹, R² groups.

[0096] The reaction between compounds of formula (II) and (III) issuitably effected in an organic solvent such as dichloromethane in thepresence of a base such as DMAP and EDC. Moderate temperatures forexample of from 0 to 50° C., conveniently ambient temperature, areemployed.

[0097] Precursor groups R^(1′) and R^(2′) may include protecting groupssuch as esters, which are not pharmaceutically acceptable. These may beconverted to hydrogen or other prodrug groups using conventional methodsas illustrated below.

[0098] Removal of protecting groups R⁵ can be carried out usingconventional methods such as reaction with TFA and/or triethylsilane.

[0099] Compounds of formula (II) are suitably prepared by deprotecting acompound of formula (IV)

[0100] where R^(1′), R³, R⁴, R⁵ and L are as defined in relation toformula (II) and R⁶ is a protecting group, in particular an alkyl groupsuch as methyl. Deprotection is suitably effected using a strong basesuch as an alkali metal hydroxide, in particular sodium hydroxide. Thereaction is suitably effected in a solvent such as aqueous alcohol andin particular aqueous methanol, at elevated temperatures, convenientlyat the reflux temperature of the solvent.

[0101] Compounds of formula (IV) where L is —CH₂NH— may be prepared bycoupling a compound of formula (V)

[0102] where R³, R⁴ and R⁶ are as defined above; with an aldehyde offormula (VI)

[0103] where R^(1′) and R⁵ are as defined above.

[0104] Suitable coupling conditions include the use of a reducing agent(e.g. NaCNBH₃, BH₃, hydrogen plus catalyst, LiHBEt₃,di-isobutyl-aluminiumhydride, lithium aluminium hydride, sodiumborohydride) in the presence of a suitable solvent e.g.methanol orethanol & acetic acid.

[0105] Aldehydes of formula (VI) may be prepared by reduction of thecompounds of formula (VII)

[0106] where R^(1′) and R⁵ are as defined above and R⁶ is alkyl such asmethyl and R⁷ is alkoxy such as methoxy.

[0107] Suitably powerful reducing agents such as lithium aluminiumhydride are employed. The reaction is carried out in a solvent such astetrahydrofuran at low temperatures, for example from −50 to 0° C., inparticular at about −20° C.

[0108] Compounds of formula (VII) are suitably prepared by reacting acompound of formula (VIII)

[0109] where R⁴ is a leaving group such a methansulphonyloxy group,which a compound of formula (IX)

[0110] where R^(1′) is as defined above and in particular is atriphenylmethyl or trityl group. Reaction conditions would be apparentto the skilled person, but in general, the reaction is effected in anorganic solvent such as dimethylformamide (DMF) at moderatetemperatures, for example of from 0 to 60° C. and preferably at about40° C.

[0111] Compounds of formula (VIII) may be prepared by reacting compoundsof formula (X)

[0112] where R⁵, R⁶ and R⁷ are as defined above, with a compound offormula (XI)

R⁸—Z  (XI)

[0113] where R⁸ is as defined above and Z is a leaving group such ashalogen, in particular chlorine. The reaction is suitably effected in anorganic solvent such as dichloromethane in the presence of a weak basesuch as triethylamine. Moderate to low temperatures, for example, from−10 to 0° C. are suitably employed.

[0114] Compounds of formula (X) are suitably prepared by reacting acompound of formula (XII)

[0115] where R⁵ is as defined above, with a compound of formula (XIII)

[0116] where R⁶ and R⁷ are as defined above. A particular example of acompound of formula (XII) is N,O-dimethylhydroxylamine. The reaction issuitably effected in the presence of a base (such as DCCI and DMAP) andin an organic solvent such as dichloromethane.

[0117] Compounds of formula (XII) may be prepared by N-protection of thecorresponding hydroxy proline derivative using known methods.

[0118] Compounds of formula (V) are suitably prepared by hydrogenationof a compound of formula (XIV)

[0119] where R³, R⁴ and R⁶ are as defined above. Hydrogenation issuitably effected in the presence of a catalyst such as a palladiumcatalyst.

[0120] Compounds of formula (XIV) are suitably prepared by reacting acompound of formula (XV)

[0121] where R⁶ is as defined above and Z′ is a leaving group such ashalogen and in particular bromine, with a compound of formula (XVI)

[0122] where R³ and R⁴ are as defined above. The reaction is suitablyeffected in the presence of a reagent such as ceasium fluoride, and acatalyst such as a palladium catalyst (e.g. tetrakis(triphenylphsophine)palladium(0). A suitable solvent for the reaction is dimethoxyethane andthe reaction can be effected under reflux conditions.

[0123] Compounds of formula (IV) where L represents —CH₂O— may beprepared by reacting a compound of formula (XVII)

[0124] where R³, R⁴ and R⁶ are as defined above,

[0125] with a compound of formula (XVIII)

[0126] where R^(1′) and R⁵ are as defined above. The reaction issuitably effected under conditions similar to those described above forthe reaction between compounds of formulae (V) and (VI).

[0127] Compounds of formula (XVIII) are suitably prepared by reductionof a compound of formula (VI), for example using a reducing agent suchas lithium aluminium hydride. Reduction is carried out underconventional conditions in a solvent such as tetrahydrofuran.

[0128] Compounds of formula (XVII) may be prepared by protection of thecorresponding carboxylic acid, for example by esterifying the acid usingan alcohol, in particular an alkyl alcohol such as methanol. Thereaction is suitably effected in the presence of sulphuryl chloride orthe like, at elevated temperatures, conveniently at the refluxtemperature of the solvent.

[0129] The acid itself may be prepared by deprotection of a compound offormula (XIX)

[0130] where R³ and R⁴ are as defined above and R¹⁰ and R¹¹ areprotecting groups such as alkyl, and in particular methyl groups.Suitable deprotection conditions include heating the compound with asuitable reagent such as pyridine hydrochloride to high temperaturessuch, for example from 200 to 250° C., and preferably at about 220° C.

[0131] Compounds of formula (XIX) are obtained by reaction of a compoundof formula (XX)

[0132] where R¹⁰ and R¹¹ are as described above and Z″ is a leavinggroup such as halogen, in particular bromine, with a compound of formula(XVI) as defined above, using conditions similar to those described forthe reaction of a compound of formula (XV) with a compound of formula(XVI).

[0133] Compounds of formula (IV) where L is —CH═CH— are suitablyprepared by reacting a compound of formula (VI) as defined above with acompound of formula (XXI)

[0134] where R³, R⁴ and R⁶ are as defined above and R¹² is a phosphateion such as diethylphosphate, or a triphenylphosphine group. Thereaction is a Wittig reaction and is suitably carried out underconventional conditions. Suitable reaction conditions include the use ofa base (e.g. potassium carbonate, metal hydride, metal alkoxide) in thepresence of an organic solvent (e.g. THF, toluene, DMSO) optionally inthe presence of an aqueous solvent (2-phase system) and optionally inthe presence of a catalyst complexing agent which solubilises alkalimetal ions in non-polar solvents such as1,4,7,10,13-pentaoxacyclopentadecane (also called 15-Crown-5) or1,4,7,10,13,16-hexaoxacyclooctadecane (also called 18-Crown-6).

[0135] Compounds of formula (XXI) are suitably obtained by reacting acompound of formula (XXII)

[0136] where R³, R⁴ and R⁶ are as defined above and Z′″ is a leavinggroup such as halogen, and in particular bromine, with a phosphite suchas triethyl phosphite. Reflux conditions are suitably employed and aninert atmosphere may be provided.

[0137] Compounds of formula (XXI) may be produced using methodsdescribed for example in PCT/GB98/00230. Preparation details aresummarised further in Scheme 2 hereinafter.

[0138] If necessary or required, groups R¹ and R² may be changed fordifferent such groups after any of the above preparation methods usingconventional chemistry and examples of this are provided hereinafter.

[0139] Biological activity was tested as follows. Farnesyl proteintransferase (FPT) was partially purified from human placenta by ammoniumsulphate fractionation followed by a single Q-Sepharose® (Pharmacia,Inc) anion exchange chromatography essentially as described by Ray andLopez-Belmonte (Ray K P and Lopez-Belmonte J (1992) Biochemical SocietyTransations 20 494-497). The substrate for FPT was Kras (CVIM C-terminalsequence). The cDNA for oncogenic val12 variant of human c-Ki-ras-2 4Bwas obtained from the plasmid pSW11-1 (ATCC). This was then subclonedinto the polylinker of a suitable expression vector e.g. pIC147. TheKras was obtained after expression in the E. coli strain, BL21. Theexpression and purification of c-KI-ras-2 4B and the val12 variant in E.coli has also been reported by Lowe et al (Lowe P N et al. J. Biol.Chem. (1991) 1672-1678).

[0140] Incubations with enzyme contained 300 nM tritiated farnesylpyrophosphate (DuPont/New England Nuclear), 120 nM ras-CVIM, 50 mM TrisHCl pH 8.0, 5 mM MgCl₂, 10 μM ZnCl₂, 5 mM dithiotheitol and compoundswere added at appropriate concentrations in DMSO (3% final concentrationin test and vehicle control). Incubations were for 20 minutes at 37° andwere stopped with acid ethanol as described by Pompliano et al.(Pompliano D L et al (1992) 31 3800-3807). Precipitated protein was thencollected onto glass fibre filter mats (B) using a Tomtec® cellharvester and tritiated label was measured in a Wallac® 1204 Betaplatescintillation counter.

[0141] Although the pharmacological properties of the compounds of theFormula I vary with structural change as expected, in general compoundsof the Formula I possess an IC₅₀ in the above test in the range, forexample, 0.01 to 200 μM.

[0142] The invention will now be illustrated in the followingnon-limiting Examples in which, unless otherwise stated:

[0143] (i) evaporations were carried out by rotary evaporation in vacuoand work-up procedures were carried out after removal of residual solidsby filtration;

[0144] (ii) operations were carried out at room temperature, that is inthe range 18-25° C. and under an atmosphere of an inert gas such asargon;

[0145] (iii) column chromatography (by the flash procedure) and mediumpressure liquid chromatography (MPLC) were performed on Merck Kieselgelsilica (Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phasesilica obtained from E. Merck, Darmstadt, Germany;

[0146] (iv) yields are given for illustration only and are notnecessarily the maximum attainable;

[0147] (v) the end-products of the Formula I have satisfactorymicroanalyses and their structures were confirmed by nuclear magneticresonance (NMR) and mass spectral techniques; chemical shift values weremeasured on the delta scale; the following abbreviations have been used:s, singlet; d, doublet; t or tr, triplet; m, multiplet; br, broad;

[0148] (vi) intermediates were not generally fully characterised andpurity was assessed by thin layer chromatographic, infra-red (IR) or NMRanalysis;

[0149] (vii) melting points are uncorrected and were determined using aMettler SP62 automatic melting point apparatus or an oil-bath apparatus;melting points for the end-products of the Formula I were determinedafter crystallisation from a conventional organic solvent such asethanol, methanol, acetone, ether or hexane, alone or in admixture; and

[0150] (viii) the following abbreviations have been used: ALLOCallyloxycarbonyl BOC tert-butoxycarbonyl DCCI1,3-dicyclohexylcarbodiimide DMA N,N-dimethylacetamide DMAP4-dimethyl-aminopyridine DMF N,N-dimethylformamide DMSOdimethylsulfoxide EDC 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimideEEDQ 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline HOBT1-hydroxybenzotriazole NMM N-methylmorpholine NMM-O4-methylmorpholine-N-oxide TFA trifluoroacetic acid THF tetrahydrofuranTMSI trimethylsilyliodide TPAP tetrapropylammonium perruthenate

EXAMPLE 1

[0151] Preparation of Compound 8 in Table 1

[0152] A mixture of Compound (xi) in Scheme 1 (0.54 g.), triethylsilane(1 ml.) and TFA (60 ml.) was stirred at ambient temperature for 1 hourunder a nitrogen atmosphere. The TFA was evaporated away and the residuedissolved in ethyl acetate (5 ml.). HCl in ether (1 M,10 ml.) was addedfollowed by more ether (50 ml.). The resulting white solid was isolatedby centrifuging, further washing with ether and re-centrifuging (3 timesin all). The solid was dried under high vac. to give Compound 8 as thehydrochloride salt (0.439 g.).

[0153] Compound 8:

[0154]¹H NMR data (DMSO d₆) δ 1.16 (6H, m), 1.60-1.95 (5H, m), 1.98 (3H,s), 2.05 (2H, m), 2.24 (2H, m), 2.43 (2H, m), 2.69 (3H, m), 2.78-3.02(3H, m), 3.14 (1H, m), 3.24-3.58 (3H, m), 3.65 (1H, m), 3.80 (1H, m),4.02 (1H, m), 4.22 (1H, m), 4.88 (1H, m), 6.54 (1H, m), 6.68 (1H, d),7.13 (2H, t), 7.23-7.38(3H, m), 8.11(1H, d).

[0155] MS (ES+) m/z 615 (M+H)⁺

[0156] The starting material (Compound (xi) in Scheme 1) was synthesisedfrom Compound (v) of Scheme 1 as described below. Compound (v) of Scheme1 had been prepared as described in Example 1 of PCT/GB99/000369.:

[0157] A mixture of Compound (v) (9.32 g.), Compound (vi) (15 g.) ofScheme 1 and 3A powdered molecular sieves (20 g.) in methanol (250 ml.)was stirred at ambient temperature under a nitrogen atmosphere for 4hours. Acetic acid (9.1 ml.) was then added followed by sodiumcyanoborohydride (3.99 g.). The mixture was then stirred for a further18 hours. The molecular sieves were filtered off and washed with moremethanol and dichloromethane. The filtrate and washings were evaporatedto dryness and the residue partitioned between sat. aqueous sodiumbicarbonate solution and dichloromethane. The organic solution was driedand evaporated to dryness. The residue was purified by flash columnchromatography using ethyl acetate/iso-hexane (20:80, 30:70) as eluantto give Compound (vii) of Scheme 1 (14 g.) as a white foam.

[0158] Compound (vii) of Scheme 1:

[0159]¹H NMR data (CDCl₃) δ 1.37 (9H, s), 1.38 (1H, m), 1.50 (1H, m),2.20-2.95 (3H, m), 3.20 (2H, m), 3.60 (3H, s), 3.95 (1H, m), 5.60 (1H,m), 6.34 (1H, m), 6.51 (1H, m), 7.02 (2H, t), 7.14-7.37 (9H, m), 7.43(8H, m), 7.80(1H, d).

[0160] MS (ES+) m/z 519.46 (M+H)⁺

[0161] A mixture of Compound (vii) (14 g.), sodium hydroxide (8 g.),water (100 ml.) and methanol (500 ml) was stirred at reflux for 18hours. The reaction mixture was reduced in volume to 100 ml, dilutedwith water (100 ml.), acidified to pH 5 with aqueous citric acid (1M)and extracted with dichloromethane (2×150 ml). The combined organicswere dried and evaporated to dryness to yield the desired acid, Compound(viii) in Scheme 1 as a white foam (12 g.).

[0162] Compound (viii) of Scheme 1

[0163]¹H NMR data (CDCl₃) δ 1.34 (1H, m), 1.36 (9H, s), 1.50 (1H, m),2.15-3.00 (3H, m), 3.20 (2H, m), 3.96 (1H, m), 5.62 (1H, m), 6.32 (1H,m), 6.50 (1H, m), 7.00 (2H, t), 7.14-7.24 (9H, m), 7.45 (8H, m), 7.88(1H, d).

[0164] A mixture of Compound (viii) (8 g.), L-methionine iso-propylester hydrochloride (3.2 g.), DMAP (7.1 g.) and EDC (2.9 g.) indichloromethane (100 ml.) was stirred at ambient temperature for 18hours. The solution was washed with aqueous citric acid (1M), brine anddried. It was then diluted with the same amount of iso-hexane andapplied directly to a silica flash column eluting with ethylacetate/iso-hexane (20:80,30:70) to give Compound (ix) (8.4 g.) as asolid white foam.

[0165] Compound (ix) of Scheme 1

[0166]¹H NMR data (DMSO d₆) δ 1.06 (6H, m), 1.26 (9H, s), 1.30 (1H, m),1.62-1-93 (3H, m), 1.98 (3H, s), 2.11-2.32 (2H, m), 2.35-3.8 (3H, m),2.94-3.50 (2H, m), 3.75 (1H, m), 4.20 (1H, m), 4.88 (1H, m), 6.20 (1H,m), 6.52 (1H, m), 6.60 (1H, d), 7.10 (2H, t), 7.16-7.41 (18H, m), 8.04(11H, d).

[0167] TFA (11.3 ml.) was added to a rapidly stirring solution ofCompound (ix) (8.4 g.) and triethylsilane (15.6 ml.) in dichloromethane(450 ml.) under a nitrogen atmosphere. The solution was then stirred atambient temperature for 4 hours, basified with sat. sodium bicarbonatesolution and the dichloromethane layer separated. After drying andevaporation to a smaller volume (50 ml.) it was applied directly to asilica flash column and eluted with ethyl acetate/iso-hexane(20:80,50:50) to give Compound (x) of Scheme 1(4.8 g.) as a white solid.

[0168] Compound (x) of Scheme 1:

[0169]¹H NMR data (CDCl₃) δ 1.20 (6H, m), 1.38 (1H, d), 1.45 (9H, s),1.50-1.83 (3H, m), 1.92 (1H, m), 2.04 (3H, s), 2.20 (2H, t), 2.60 (1H,m), 3.06 (1H, m), 3.18-3.34 (2H, m), 4.02 (1H, m), 4.20 (1H, m), 4-56(1H, m), 4.95(1H, m), 5.49(1H, m), 5.80(1H, d), 6.43(1H, m), 6.61(1H,d), 7.1(2H, t), 7.35(2H, m), 7.6(1H, d).

[0170] MS (ES+) m/z 620.59 (M+H)⁺

[0171] A mixture of Compound (x) of Scheme 1 (500 mg.),N-methylpiperidine-4-carboxylic acid (218 mg), N-methylmorpholine (409mg), EDC (232 mg) and HOBT (109 mg) in dichloromethane (100 ml.) wasstirred at ambient temperature under a nitrogen atmosphere for 18 hours.It was then applied directly to a silica flash column and eluted withethyl acetate/iso-hexane (1:1), ethyl acetate, methanol/ethyl acetate(10:90,20:80) to give Compound (xi) in Scheme 1 (540 mg.) as a whitefoam.

[0172] Compound (xi) in Scheme 1:

[0173]¹H NMR data (DMSO d₆) δ 1.56 (6H, m), 1.38 (9H, s), 1.58 (2H, m),1.70-1.97 (6H, m), 1.99 (3H, s), 2.11 (3H, s), 2.25 (2H, m), 2.45 (2H,m), 2.72 (2H, m), 2.95-3.20 (2H, m), 3.28(1H, m), 3.50 (1H, m),3.70-4.07 (3H, m), 4.21 (1H, m), 4.88(1H, m), 6.28(1H, br.s.),6.47-6.70(2H, m), 7.11(2H, t), 7.23(1H, d), 7.3(2H, m ), 8.06(1H, d).

[0174] MS (ES+) m/z 745 (M+H)⁺

EXAMPLE 2

[0175] Preparation of Compound 9 in Table 1

[0176] Compound 9 was synthesised from Compound (xxii) in Scheme 2 usinga method analogous to that described in Example 1.

[0177] Compound 9

[0178]¹H NMR data (DMSO d₆) δ 1.90 (2H, m), 1.98 (3H, s), 1.99 (3H, s),2.01-2.28 (2H, m), 2.70 (3H, m), 3.02 (2H, m), 3.33 (2H, m), 3.68 (1H,m), 3.93 (2H, m), 4.38 (4H, m), 4.81 (1H, m), 4.98 (1, m), 6.58 (1H,dd), 6.90 (1H, d), 7.20 (2H, m), 7.40 (2H, m), 7.46 (1H, m), 7.54 (1H,m), 7.62 (1H, dd), 8.24 (1H, m), 8.66 (1H, dd), 8.83 (1H, m), 9.06 (1H,d).

[0179] MS (ES+) m/z 677 (M+H)⁺

[0180] The starting material (compound (xxii)) was synthesised fromCompound (xvi) in Scheme 2 as described hereinafter. The preparation ofCompound (xvi) is given as Example 14 of PCT/GB98/00230.

[0181] Compound (xvi) (20 g) was dissolved in triethyl phosphite (110ml) and heated to 160° C. under a nitrogen atmosphere for 18 hours. Thesolution was evaporated to dryness and the residue was dissolved indichloromethane and applied directly to a silica flash column and elutedwith ethyl acetate/iso-hexane (50:50) and ethyl acetate to give Compound(xvii) as a colourless oil (20.7 g).

[0182] Compound (xvii) in Scheme 2:

[0183]¹H NMR data (DMSO d₆) δ 1.16 (6H, t), 3.34 (2H, d), 3.58 (3H, s),3.94 (4H, m), 7.19-7.34 (5H, m), 7.39 (1H, m), 7.71 (1H, d).

[0184] MS (ES+) m/z 381.3 (M+H)⁺

[0185] Compound (xvii) (18.0 g) was dissolved in tetrahydrofuran (500ml) and cooled to −30° C. Potassium tert-butoxide (47.3 ml of a 1.0Msolution in tetrahydrofuran) was added over 10 minutes and then asolution of compound (vi) (22.4 g) in tetrahydrofuran (15 ml) was addedover 8 minutes. After 10 minutes aqueous saturated ammonium chloridesolution (200 ml) was added and the reaction mixture allowed to warm toambient temperature. The organic layer was separated, the aqueous washedwith ethyl acetate (100 ml) and the combined organics dried andevaporated to dryness. Purification by flash column chromatography usingethyl acetate/iso-hexane (10:90, 15:85 then 20:80) as eluant gaveCompound (xviii) in Scheme 2 as a colourless foam (24 g).

[0186] Compound (xviii) in Scheme 2

[0187]¹H NMR data (DMSO d₆) δ 1.22 (3H, bs), 1.28 (1H, m), 1.60 (1H, m),2.48-3.20 (3H, m), 3.58 (3H, s), 4.10 (1H, m), 6.23-6.45 (2H, m),7.18-7.42 (20H, m), 7.45 (1H, d), 7.72 (1H, d).

[0188] MS (ES+) m/z 699 (M+H)⁺

[0189] Compound (xviii) was converted to compound (xxii) in Scheme 2 bythe route analogous to that described in Example 1 for the preparationof Compound (xi) using the appropriate intermediates.

[0190] Compound (xix) of Scheme 2:

[0191]¹H NMR data (DMSO d₆) δ: 1.15-1.35 (10H, m), 1.52-1.65 (1H, m),2.66-2.81 (3H, m), 4.09 (1H, m), 6.27 (1H, dd), 6.40 (1H, d), 7.15-7.39(20H, m), 7.41 (1H, dd), 7.70 (1H, d), 12.69 (1H, s).

[0192] MS (ES+) m/z 686.6 (M+H)⁺

[0193] Compound (xx) in Scheme 2:

[0194]¹H NMR data (DMSO d₆) δ 1.22 (10H, bs), 1.57 (3H, m), 1.80 (4H,m), 1.98 (3H, s), 2.16 (3H, s), 2.18-2.28 (4H, m), 2.58 (1H, m), 2.75(4H, m), 4.08 (1H, m), 4.30 (1H, m), 4.70 (1H, m), 6.24 (1H, dd), 6.40(1H, d), 7.18 (2H, m), 7.21-7.47 (20H, m), 8.57 (1H, bd).

[0195] Compound (xxi) in Scheme 2

[0196]¹H NMR data (DMSO d₆) δ 1.39 (10H, bs), 1.63-1.80 (6H, m),1.81-1.98 (3H, m), 2.02 (3H, s), 2.19 (2H, m), 2.32 (3H, s), 2.63 (3H,m), 3.20 (1H, m), 3.30 (1H, m), 4.02 (1H, m), 4.40 (1H, m), 4.62 (1H,m), 4.78 (1H, m), 5.96 (1H, d), 6.25 (1H, m), 6.50 (1H, m), 7.10 (2H,t), 7.30 (1H, s), 7.39 (3H, m), 7.63 (1H, d).

[0197] MS (ES+) m/z 672 (M+H)⁺

[0198] Compound (xxii) in Scheme 2

[0199]¹H NMR data (DMSO d₆) δ 1.43 (9H, s), 1.63-2.09 (5H, m), 2.20 (2H,m), 2.26 (3H, s), 2.27 (3H, s), 2.40 (2H, m), 2.60 (2H, m), 2.79 (1H,m), 3.42 (1H, m), 3.70 (2H, dd), 4.18 (2H, m), 4.61 (2H, m), 4.68 (1H,m), 5.98 (1H, d), 6.25 (1H, dd), 6.52 (1H, d), 7.10 (2H, t), 7.38 (4H,m), 7.62 (1H, d), 8.15 (1H, m), 8.79 (1H, dd), 9.13 (1H, dd).

[0200] MS (ES+) m/z 777 (M+H)⁺

EXAMPLE 3

[0201] Preparation of Compound 5 in Table 1

[0202] Compound 5 in Table 1 was synthesised from Compound (xxv) inScheme 2 using a method analogous to that described in Example 1 for thepreparation of Compound (8).

[0203] Compound 5:

[0204]¹H NMR data (DMSO d₆) δ: 1.16 (6H, m), 1.72-1.96 (4H, m), 1.97(3H, s), 1.99-2.10 (2H, m), 2.11-2.29 (2H, m), 2.42 (1H, m), 2.53-2.74(4H, m), 2.78-3.01 (2H, m), 3.10-3.20 (1H, m), 3.29-3.45 (2H, m),3.64-3.76 (1H, m), 4.01-4.12 (1H, m), 4.22-4.40 (2H, m), 4.88 (1H, m),6.52 (1H, dd), 6.86 (1H, d), 7.14-7.22 (2H, t), 7.36-7.47 (4H, m), 7.52(1H, d), 8.58 (1H, d).

[0205] MS (ES+) m/z 642.6 (M+H)⁺

[0206] Compound (xxv) in Scheme 2 was synthesised from Compound (xix) bythe route described in Example 2 for the preparation of Compound (xxii)using the appropriate intermediates.

[0207] Compound (xxiii) of Scheme 2:

[0208]¹H NMR data (DMSO d₆) δ: 1.10-1.19 (6H, m), 1.20-1.30 (10H, m),1.60 (1H, m), 1.72-1.86 (2H, m), 1.96 (3H, s), 2.12-2.27 (2H, m), 2.50(1H, m), 2.68-2.80 (2H, m), 4.04 (1H, br s), 4.26 (1H, m), 4.88 (1H, m),6.25 (1H, dd), 6.40 (1H, d), 7.10-7.44 (22H, m), 8.53 (1H, d).

[0209] MS (ES+) m/z 859.5 (M+H)⁺

[0210] Compound (xxiv) of Scheme 2:

[0211]¹H NMR data (DMSO d₆) δ: 1.16 (6H, m), 1.21-1.41 (10H, m),1.63-1.86 (3H, m), 1.97 (3H, s), 2.11-2.27 (2H, m), 2.45-2.59 (1H, m),2.90 (1H, d), 3.01-3.11 (1H, t), 3.80-3.89 (1H, m), 4.21-4.34 (2H, m),4.83-4.94 (1H, m), 6.35 (1H, dd), 6.48 (1H, d), 7.15 (2H, t), 7.34-7.48(5H, m), 8.53 (1H, d).

[0212] MS (ES+) m/z 617.6 (M+H)⁺

[0213] Compound (xxv) of Scheme 2:

[0214]¹H NMR data (DMSO d₆) δ 1.16 (6H, m), 1.25-1.40 (9H, br s),1.48-1.61 (2H, m), 1.71-1.91 (6H, m), 1.97 (3H, s), 2.09 (3H, s),2.10-2.29 (2H, m), 2.39-2.47 (1H, m), 2.54-2.61 (1H, m), 2.65-2.74 (2H,m), 3.08-3.17 (1H, m), 3.28 (1H, m), 3.80-3.95 (2H, m), 4.21-4.30 (1H,m), 4.35-4.45 (1H, m), 4.88 (1H, m), 6.33 (1H, dd), 6.48 (1H, d),7.12-7.20 (2H, t), 7.34-7.48 (5H, m), 8.54 (1H, d).

EXAMPLE 4

[0215] Preparation of Compound 4 in Table 1

[0216] To a solution of Compound (xxxvi) in Scheme 3 (2.85 g.) indichloromethane (130 ml.), with sufficient methanol added to causedissolution, was added water (0.183 ml.) and the solution de-gassed withnitrogen. A catalytic quantity of bis(triphenylphosphine)palladium(II)dichloride (45 mg.) was added and the pale yellow solution stirred atambient temperature for 10 minutes before tributyltin hydride (5 ml.)was added. After 30 minutes the reaction was concentrated in vacuo (10ml.) and the reaction mixture purified by flash column chromatographyeluting with methanol/dichloromethane (10:90-30:70) to give a paleyellow foam. This was re-dissolved in ethyl acetate and HCl in ether(1M.) added. The white precipitate formed was isolated by centrifuging,washing with more ether and re-centrifuging (3 times in all) and finallydrying to give Compound 4 (1.3 g.) as a pale yellow foam.

[0217]¹H NMR data(free base) (DMSO d₆) δ 1.75-1.85 (4H, m), 1.95 (3H,s), 2.15 (3H, s), 2.15-2.3 (4H, m), 2.5-2.6 (3H, m), 2.8 (1H, dd), 3.35(2H, dd), 3.5-3.6 (2H, m), 3.85-4.05 (4H, 2×m), 4.2-4.3 (1H, m), 4.6-4.7(1H, m), 6.9 (1H, d), 7.0 (1H, dd), 7.1-7.3 (4H, 2×m), 7.35-7.4 (3H, m),7.45-7.55 (2H, m), 7.65-7.75 (1H, m), 7.9 (1H, d), 8.4 (1H, d).

[0218] MS (ES+) m/z 680 (M+H)⁺

[0219] The starting material (Compound (xxxvi)) was synthesised asfollows.

[0220] Triethylamine (29 ml.) was added to a solution of methyl4-methoxysalicylate (Compound xxvi in Scheme 3) (25.0 g.) indichloromethane (500 ml.) and the solution cooled to 0° C.Trifluoromethanesulphonic anhydride (29 ml.) was added dropwise and thereaction stirred at ambient temperature for 1 hour. Additional portionsof triethylamine and trifluoromethanesulphonic anhydride were added over16hours until HPLC showed absence of starting material. The reaction waswashed with 2N hydrochloric acid and the organic phase evaporated togive a brown oil. Purification by flash chromatography (ethylacetate/iso-hexane (50:50) gave methyl4-methoxy-2-trifluoromethylsulphonyloxybenzoate (Compound xxvii) as apale yellow oil (23.4 g).

[0221]¹H NMR data (CDCl₃,) δ 3.88 (3H, s), 3.93 (3H, s), 6.79 (1H, d),6.96 (1H, dd), 8.06 (1H, d).

[0222] MS (ES+) m/z 315 (M+H)⁺

[0223] Saturated aqueous sodium hydrogen carbonate solution (50 ml) wasadded to a solution of methyl4-methoxy-2-trifluoromethanesulphonylbenzoate (6.3 g.) and4-fluorobenzeneboronic acid (3.36 g.) in DME (150 ml) at ambienttemperature under an argon atmosphere. Tetrakis(triphenylphosphine)palladium (928 mg.) was added and the reaction heated and stirred atreflux for 3.5 hours resulting in a homogeneous solution. After coolingto ambient temperature, the reaction was partitioned between ethylacetate and water. The organic phase was washed with 2N hydrochloricacid, water and brine, filtered through 1PS filter paper and the solventremoved to give methyl 4-methoxy-2-(4-fluorophenyl)benzoate as ayellow-oily solid (7.2 g) which was used without further purification.

[0224]¹H NMR data (CDCl₃,) δ 3.65 (3H, s), 3.87 (3H, s), 6.79 (1H, d),6.91 (1H, dd), 7.08 (2H, dd), 7.25 (2H, dd), 7.90 (1H, d).

[0225] MS (ES+) m/z 261 (M+H)⁺

[0226] To a solution of methyl 4-methoxy-2-(4-fluorophenyl)benzoate (9.8g.) in methanol (75 ml.) was added 2N aqueous sodium hydroxide solution(45 ml.) and the mixture heated at reflux for 1.5 hours. The reactionwas cooled to ambient temperature, filtered and the filtrateconcentrated to remove the methanol. The residual aqueous phase waswashed with ether, acidified to pH 1 using concentrated hydrochloricacid and extracted with ethyl acetate. The organic extracts were driedand the solvent removed to give 4-methoxy-2-(4-fluorophenyl)benzoic acid(Compound (xxix) in Scheme 3) as a white solid (7.7 g), which was usedwithout further purification.

[0227]¹H NMR data (DMSO d₆,) δ 3.80 (3H, s), 6.80 (1H, d), 6.98 (1H,dd), 7.18 (2H, dd), 7-31 (2H, dd), 7.76 (1H, d).

[0228] MS (ES+) m/z 247 (M+H)⁺

[0229] A solution of boron tribromide in dichloromethane (1M, 66 ml.)was added dropwise to a stirred solution of4-methoxy-2-(4-fluorophenyl)benzoic acid (7.7 g.) in drieddichloromethane (215 ml) under an argon atmosphere at 0° C. The reactionwas stirred for 1 hour at 0° C., allowed to warm to ambient temperatureand stirred for 16 hours. The reaction was poured into ice water andextracted with dichloromethane followed by ethyl acetate. The combinedorganic extracts were washed with saturated aqueous sodium hydrogencarbonate and the aqueous phase acidified to pH 1 with concentratedhydrochloric acid and extracted with ethyl acetate. The ethyl acetateextracts were dried and evaporated to dryness to give4-hydroxy-2-(4-fluorophenyl)benzoic acid (Compound xxx) as a yellow oil(4.5 g), which was used without further purification.

[0230]¹H NMR data (DMSO d₆) δ 6.63 (1H, d), 6.80 (1H, dd), 7.15 (2H,dd), 7.26 (2H, dd), 7.71 (1H, d).

[0231] MS (ES+) m/z 233 (M+H)⁺

[0232] Sulphuryl chloride (44 ml.) was added to compound (xxx) (21.7 g.)in methanol (220 ml.) and the solution was refluxed and stirred for 18hours. The methanol was evaporated away and the residue was partitionedbetween ethyl acetate and saturated sodium bicarbonate. The organicphase was washed with brine, filtered through phase separating paper andevaporated to dryness to give compound (xxxi) as a white solid (18.2 g.)

[0233]¹H NMR data (CDCl₃,) δ 3.65 (3H, s), 5.5 (1H, br s), 6.75 (1H, d),6.85 (1H, dd), 7.05 (2H, dd), 7.25 (2H, dd), 7.85 (1H, d).

[0234] MS (ES+) m/z 247 (M+H)⁺

[0235] A solution of diethyl azodicarboxylate (7.44 g. indichloromethane (50 ml.)) was added dropwise to a stirred solution ofcompound (xxxi) (10 g.), compound (xxxii) (14.2 g.) and triphenylphosphine (11.21 g.) in dichloromethane (200 ml.) cooled to 0° C. undera nitrogen atmosphere. The reaction was then stirred at 0° C. for afurther 30 minutes and at ambient temperature for 18 hours. The reactionmixture was reduced in volume to 60 ml. and applied directly to a silicaflash column which was eluted with ethyl acetate/iso-hexane(20:80-50:50) to give compound (xxxiii) as a colourless oil (20.3 g.).

[0236]¹H NMR data (CDCl₃,) δ 1.45 (9H, s), 2.05-2.15 (1H, m), 2.55-2.7(1H, m), 3.25-3.35 (1H, m), 3.6 (3H, s), 3.75-3.8 (1H, m), 4.05-4.2 (2H,m), 4.2-4.3 (2H, m), 4.55 (2H, d), 5.2 (1H, d), 5.3 (1H, d), 5.8-6.0(1H, m), 6.8 (1H, m), 6.9 (1H, m), 7.05 (2H, dd), 7.25 (2H, dd), 7.9(1H, d).

[0237] MS (ES+) m/z 546 (M+H)⁺

[0238] A mixture of compound (xxxiii) (10 g.), 2N aqueous sodiumhydroxide (23 ml.), water (70 ml.) and methanol (150 ml.) was heated atreflux for 18 hours. More 2N sodium hydroxide (5 ml.) and water (30 ml.)was added and the reaction mixture heated at reflux for another 24hours. The mixture was cooled to ambient temperature, the methanolevaporated away and the aqueous residue washed with ether and acidifiedto pH 2 with 2N hydrochloric acid. It was then extracted with ethylacetate, dried and evaporated to dryness to give compound (xxxiv) as acolourless gum (7.51 g.)

[0239]¹H NMR data (DMSO d₆) δ 1.8-1.9 (1H, m), 2.5-2.6 (1H, m), 3.0-3.15(1H, m), 3.3-3.4 (1H, m), 3.9 (1H, dd), 4.05-4.15 (1H, m), 4.2-4.3 (2H,m), 4.5 (2H, m), 5.1-5.25 (2H,m), 5.8-6.0 (1H, m), 6.8 (1H, m), 7.0 (1H,dd), 7.2 (2H, dd), 7.35 (2H, dd), 7.8 (1H, d).

[0240] MS (ES+) m/z 432 (M+H)⁺

[0241] To a solution of Compound (xxxiv) (7.5 g.) in dry dichloromethane(400 ml) under nitrogen was added triethylamine (4.84 ml.) followed bybenzoyl chloride (2.12 ml.) and the reaction stirred at ambienttemperature for 16hours. The reaction was quenched with 2N HCl andextracted with ethyl acetate. The combined organics were washed withbrine, dried and concentrated in vacuo to give Compound (xxxv) as a paleyellow foam (9.35 g).

[0242] MS (ES+) m/z 536 (M+H)⁺

[0243] Compound (xxxv) was converted to Compound (xxxvi) using a methodanalogous to that described in Example 2 above for the preparation ofCompound (xx).

[0244]¹H NMR data (CDCl₃) δ 1.7-1.9 (3H, m), 1.99-2.05 (2H, m), 2.05(3H, 2×s), 2.15-2.25 (4H, m), 2.45 (3H, s), 2.6-2.85 (4H, 2×br.m), 3.4(1H, dd), 4.1-4.45 (5H, 2×m), 4.55-4.6 (3H, m), 4.8-4.9 (1H, br.m), 5.2(1H, d), 5.3 (1H, d), 5.9 (1H, d), 5.9-6.0 (1H, m), 6.85 (1H, m), 6.95(1H, m), 7.1 (2H, dd), 7.35-7.5 (5H, m), 7.6 (1H, dd), 7.6 (1H, d), 7.9(2H, d).

[0245] MS (ES+) m/z 764 (M+H)⁺

EXAMPLE 5

[0246] Pharmaceutical Compositions

[0247] The following illustrate representative pharmaceutical dosageforms of the invention as defined herein (the active ingredient beingtermed “Compound X”), for therapeutic or prophylactic use in humans: (a)Tablet I mg/tablet Compound X 100 Lactose Ph. Eur 182.75 Croscarmellosesodium 12.0 Maize starch paste (5% w/v paste) 2.25 Magnesium stearate3.0 (b) Tablet II mg/tablet Compound X 50 Lactose Ph. Eur 223.75Croscarmellose sodium 6.0 Maize starch 15.0 Polyvinylpyrrolidone (5% w/vpaste) 2.25 Magnesium stearate 3.0 (c) Tablet III mg/tablet Compound X1.0 Lactose Ph. Eur 93.25 Croscarmellose sodium 4.0 Maize starch paste(5% w/v paste) 0.75 Magnesium stearate 1.0 (d) Capsule mg/capsuleCompound X 10 Lactose Ph. Eur 488.5 Magnesium 1.5 (e) Injection I (50mg/ml) Compound X 5.0% w/v 1 M Sodium hydroxide solution 15.0% v/v 0.1 MHydrochloric acid (to adjust pH to 7.6) Polyethylene glycol 400 4.5% w/vWater for injection to 100% (f) Injection II (10 mg/ml) Compound X 1.0%w/v Sodium phosphate BP 3.6% w/v 0.1 M Sodium hydroxide solution 15.0%v/v Water for injection to 100% (g) Injection III (1 mg/ml, buffered topH 6) Compound X 0.1% w/v Sodium phosphate BP 2.26% w/v Citric acid0.38% w/v Polyethylene glycol 400 3.5% w/v Water for injection to 100%(h) Aerosol I mg/ml Compound X 10.0 Sorbitan trioleate 13.5Trichlorofluoromethane 910.0 Dichlorodifluoromethane 490.0 (i) AerosolII mg/ml Compound X 0.2 Sorbitan trioleate 0.27 Trichlorofluoromethane70.0 Dichlorodifluoromethane 280.0 Dichlorotetrafluoroethane 1094.0 (j)Aerosol III mg/ml Compound X 2.5 Sorbitan trioleate 3.38Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0Dichlorotetrafluoroethane 191.6 (k) Aerosol IV mg/ml Compound X 2.5 Soyalecithin 2.7 Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0Dichlorotetrafluoroethane 191.6 (l) Ointment ml Compound X 40 mg Ethanol300 μl Water 300 μl 1-Dodecylazacycloheptan-2-one 50 μl Propylene glycolto 1 ml

[0248] Note

[0249] The above formulations may be obtained by conventional procedureswell known in the pharmaceutical art. The tablets (a)-(c) may be entericcoated by conventional means, for example to provide a coating ofcellulose acetate phthalate. The aerosol formulations (h)-(k) may beused in conjunction with standard, metered dose aerosol dispensers, andthe suspending agents sorbitan trioleate and soya lecithin may bereplaced by an alternative suspending agent such as sorbitan monooleate,sorbitan sesquioleate, polysorbate 80, polyglycerol oleate or oleicacid.

1. A compound of formula (I)

wherein: R¹ and R² are independently selected from H or a prodrugmoiety; R³ is hydrogen or halogen; R⁴ is hydrogen or halogen; L is—CH═CH— or —CH₂—Z— where Z is NH or O; Y is S, S(O) or S(O)₂; or a saltthereof, provided that at least one of R³ or R⁴ is other than hydrogen.2. A compound of formula (I) as claimed in claim 1 wherein the group R¹is hydrogen or prodrug group of formula R⁵C(O)— where R⁵ is anoptionally substituted aryl or heterocyclyl group.
 3. A compound offormula (I) as claimed in claim 2 wherein R⁵ is optionally substitutedphenyl, optionally substituted pyridyl, optionally substituted furyl,optionally substituted isoxazole, optionally substitutedtetrahydropyridyl or optionally substituted tetrahydrofuryl.
 4. Acompound of formula (I) as claimed in claim 3 wherein R⁵ is phenyl,pyridyl or N-methylpiperidine.
 5. A compound of formula (I) as claimedin claim 2, 3 or 4 wherein R⁵ is optionally substituted by alkyl,haloalkyl, hydroxy, alkoxy or cyano.
 6. A compound of formula (I) asclaimed in any claim from 1 to 5 wherein R² together with the carboxygroup to which it is attached forms a pharmaceutically-acceptable esteror amide.
 7. A compound of formula (I) as claimed in 6 wherein R²together with the carboxy group to which it is attached forms aC₁₋₆alkyl ester or C₁₋₆cycloalkyl ester; C₁₋₆alkoxymethyl ester;C₁₋₆alkanoyloxymethyl ester; phthalidyl ester;C₃₋₈cycloalkoxycarbonyloxyC₁₋₆alkyl ester; 1,3-dioxolan-2-ylmethylester; C₁₋₆alkoxycarbonyloxyethyl ester; aminocarbonylmethyl ester andmono- or di-N—(C₁₋₆alkyl) versions thereof; or a pharmaceuticallyacceptable ester of an optionally substituted heterocyclic group.
 8. Acompound of formula (I) as claimed in claim 6 wherein R² together withthe carboxy group to which it is attached forms N—C₁₋₆alkylamide orN,N-di-(C₁₋₆alkyl)amide.
 9. A compound of formula (I) as claimed in anyclaim from 1 to 5 wherein R² is selected from hydrogen, a C₁₋₄alkylgroup, or an optionally substituted heterocyclic group.
 10. A compoundof formula (I) as claimed in any claim from 5 to 9 wherein R³ is a haloatom.
 11. A compound of formula (I) as claimed in in any claim from 5 to9 wherein R⁴ is hydrogen or fluorine.
 12. A compound of formula (I) asclaimed in in any claim from 5 to 9 wherein the linking group L is—CH═CH—.
 13. A compound of formula (I) as claimed in in any claim from 5to 9 wherein the Y is S or S(O)₂.
 14. A compound of formula (I)

wherein: R¹ and R² are independently selected from H or a prodrugmoiety; R³ is hydrogen or halogen; R⁴ is hydrogen or halogen; L is—CH═CH— or —CH₂—Z— where Z is NH or O; Y is S, S(O) or S(O)₂; or a saltthereof.
 15. A compound as defined in any claim from 1 to 14 for use asa medicament.
 16. A pharmaceutical composition comprising a compound asdefined in any claim from 1 to 14 together with a pharmaceuticallyacceptable diluent or carrier.